Calcium plays a critical role as an intracellular signal, and controls many different cell processes, of which calcium appears to play an important role in cell growth [Berridge, M. J., et al., Nat. Rev. Mol. Cell Biol. 2003, 4, 517-529]. For example, it has also been shown that calcium signaling is required for cell cycle progression from G1/S phase through mitosis. It has been demonstrated that depletion of intracellular calcium arrests the cell cycle in the G0/G1 and S interphases [Clapham, D. E. Cell 1995, 80, 259-268]. Regulation of the changes in intracellular calcium has been proposed to be via a T-type calcium channel. Lined with this proposition, it has recently been reported that T-type calcium channel blockers (CCBs) inhibited cellular proliferation [McCalmont, W. F., et al., Bioorg. Med. Chem. Lett. 2004, 14, 3691-3695; McCalmont, W. F., et al., Bioorg. Med. Chem. 2005, 13, 3821-3839]. Opposed to T-type CCBs, however, it remains to discussion that some L-type CCBs as anti-hypertensive agents may be related to the risk of cancer in the elderly and promote growth of pre-existing cancer cells in human by inhibition of apoptosis [La Vecchia, C. et al., Eur. J. Cancer 2003, 39, 7-8]. Therefore, selective T-type CCBs could be another tool to treat cancer where the cell cycle has become aberrant.
On the other hand, it has been reported that over-expression of T-type calcium channel may cause epilepsy (Tsakiridou, E. et al., J. Neurosci. 1995, 15, 3110-3117), high blood pressure (Self, D. A. et al., J Vacs. Res. 1994, 31, 359-366), ventricular hypertrophy (Nuss, H. B. et al. , Circ Res. 1995, 73, 777-7825), pain (Shin, H. S. et al., Science 2003, 302, 117-119) and angina pectoris (Van der Vring, J. A. et al., Am. J. Ther. 1999, 6, 229-233). Therefore, selective T-type calcium channel blockers could be used for preventing or treating epilepsy, high blood pressure, ventricular hypertrophy, pain and angina pectoris.